Method for producing azetidinone and cephalosporin derivatives

ABSTRACT

New compounds are disclosed having the general formulas (1) and (2): ##STR1## Also described is a process for preparing the compounds of formulas (1) and (2). Further described is a process for preparing a cephalosporin derivative having formula (5): ##STR2## by converting the compound of formula (1) to the compound of formula (2) and then converting the compound of formula (2) to the compound of formula (5).

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. Ser. No.07/836,527, filed Feb. 18, 1992, now abandoned.

FIELD OF THE INVENTION

The present invention is directed to azetidinone derivatives having thegeneral formulas (1) and (2) as set forth below: ##STR3##

In the thiazolidine-azetidinone derivatives expressed by general formula(1) above, R¹ can be a substituted aryl group, an unsubstituted arylgroup, a substituted aryloxy group and an unsubstituted aryloxy group;R² CO can be a carboxyl residue: and R³ can be a hydrogen atom orcarboxylic protective group.

In the azetidinone derivatives expressed by the general formula (2)above, R³ can be a hydrogen atom or a carboxylic protective group, andAr can be an unsubstituted or substituted aryl group.

The present invention is also directed to methods of preparingazetidinone derivatives expressed by general formulas (1) and (2), aswell as methods of using these azetidinone derivatives to preparedcephalosporin derivatives such as those expressed by general formula (5)below: ##STR4## (where R³ has already been defined).

BACKGROUND OF THE INVENTION

It is known that the cephalosporin derivatives represented by compound(5) are important intermediates that can readily be transformed intovarious types of cephalosporin antibiotics, such as cefazolin,cefmetazole, cefamandole, cefotiam, cefmenoxime, ceftriaxone,cefbuperazone, cefuzonam and cefminox. This can be accomplished by aprocesses such as acylation of the amino group at the 7 position,substitution of the chloromethyl group at the 3 position with anaromatic heterocyclicthiol, and removal of the carboxylic protectivegroup. Therefore, the compound (5) is valued highly in industry.

Chloro compounds are known in the art. Examples are those cited by R. D.G. Cooper (Tetrahedron Lett., 21, 781 (1980)) and by Shigeru Torii andothers (Japanese Unexamined Patent Publication Nos. 57-59896, 57-59897,and 59-55888). These examples concern thiazolidine azetidinonederivatives represented by formula (6): ##STR5## The chloro compounds offormula (6) differ from the thiazolidine azetidinone derivatives of thepresent invention which are a totally new compounds.

Other known chloro derivatives include those shown by Torii, et al.(Japanese Unexamined Patent Publication Nos. 58-85894 and 59-164771).These derivatives are expressed by the general formula (7) below. Thesederivatives all include a form where the amino groups are protected byacyl groups as shown in formula (7) below: ##STR6## Thus, an extraprocess of disconnecting this acyl group becomes necessary at the end ofthe process. The present invention requires no such extra process.

SUMMARY OF THE INVENTION

An object of the present invention is to efficiently preparethiazolidine-azetidinone derivatives, whose methyl groups at the allylicposition can be chlorinated, as shown in general formula (1), by asimple process of chlorination of the methyl groups of the allylposition of the thiazolidine-azetidinone derivatives, which areexpressed by general formula (3) as shown below. An additional objectiveof the present invention is the transformation of this syntheticintermediate (1) into azetidinone derivatives expressed by generalformula (2), which a synthetic precursor for the cephalosporinderivative (5), at a high yield by applying a simple method.

DETAILED DESCRIPTION OF THE INVENTION

The thiazolidine-azetidinone expressed by general formula (1): ##STR7##(where R¹, R², and R³ already have been defined) can be produced througha reaction between a chlorinating agent and a thiazolidine azetidinonederivative defined by general formula (3) in an organic solvent:##STR8## where R¹ is a substituted aryl group, an unsubstituted arylgroup, a substituted aryloxy group, and an unsubstituted aryloxy group;R² CO is a carboxyl residue, and R³ is a hydrogen atom or carboxylicprotective group.

The azetidinone derivatives expressed by general formula (2): ##STR9##(where R³ and Ar have already been defined) can be produced through areaction between the compound of general formula (1) and an arylsulfinicacid expressed by general formula (4):

    Ar--SO.sub.2 H                                             (4)

(where Ar has already been defined) in the presence of an acid in anorganic solvent that contains a lower alcohol.

The thiazolidine-azetidinone derivatives (1) and the azetidinonederivatives (2) are not known and have not been described in the priorart. Thiazolidine-azetidinone derivatives expressed by general formula(1) and azetidinone derivatives expressed by general formula (2) areimportant intermediates of cephalosporin antibiotics and can betransformed into cephalosporin derivatives (5) as shown in followingreaction scheme (A): ##STR10## where R¹, R², R³ and Ar are definedabove.

The reaction conditions for transforming the thiazolidine-azetidinonederivative of formula (1) into the azetidinone derivative of formula (2)is described elsewhere in this application. The compound represented byformula (2) can be convened into the compound represented by formula (5)by reaction In the presence of a base. For example, compound (2) can beadded to a solvent containing a base having a molar quantity of about1.1 to about 1.5 relative to compound (2). The reaction can be carriedout at a temperature from about -50° C. to 5° C. for about 5 to about 30minutes. Suitable bases include ammonia, ammonia water potassiumhydroxide, sodium hydroxide, potassium acetate, sodium acetate,triethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene,1,5-diazabicyclo[4.3.0]non-5 ene, potassium iodide and sodium iodide.Suitable solvents include dimethylformamide, dimethylacetamide,methanol, ethanol, 2-propanol, acetonitrile, butyronitrile, acetone andmethyl ethyl ketone.

The starting material (3) used in the present invention is a compoundthat can be readily synthesized from penicillin sulfoxide (8), as shownin reaction scheme (B). Specifically, compound (8) is transformed intocompound (9) by a method proposed by R. D. G. Cooper, et al (J. Am.Chem. Soc., 92, 2575 (1970)) and compound (3) from compound (9) viacompound (10) by a method cited by S. J. Eagle, et al. (TetrahedronLett., 1978, 4703). ##STR11##

For example, a compound represented by formula (8), penicillinsulfoxide, can be reacted with trimethyl phosphite in refluxing benzenefor a period of time such as 30 hours to obtain a compound representedby formula (9). The compound (9) can be acylated (e.g., in a Ac₂ O/HCOOHreaction medium) to give the compound represented by formula (10) inhigh yields. Oxidation of compound (10) with peracetic acid (CH₃ CO₃ H)provides a quantitative yield of the compound represented by formula(3).

For the thiazolidine azetidinone derivatives (3) and (1) used in thepresent invention, no particular restrictions are placed on R¹, R², andR³ and the protection groups which are commonly used inpenicillin-cephalosporin conversion are applicable. Examples of R¹include aryl groups such as phenyl, paranitrophenyl, andparachlorophenyl groups with or without substitutions or substituents.Examples of R² include an hydrogen atom and lower alkyl groups such asmethyl group, ethyl group, and n-butyl group; and aryl groups such asphenyl, paratolyl, paranitrophenyl, and parachlorophenyl groups with orwithout substitutions or substituents. Examples of R³ includephenylmethyl groups such as benzyl, paranitrobenzyl, paramethoxybenzyl,and diphenylmethyl groups with or without substitutions or substituents;and low alkyl groups such as methyl, ethyl, tertiary butyl, with orwithout halogen substituents, such as 2,2,2-trichloroethyl.

In the method of the present invention where the methyl group at theallyl position Is chlorinated in the process of converting the compoundrepresented by formula (3) to the compound represented by formula (1),the thiazolidine azetidinone derivative (3) is dissolved in an organicsolvent at a concentration of 1 mol/1 liter to 0.01 mol/1 liter,followed by a reaction of a chlorinating agent. Any suitablechlorinating agent can be used, such as tertiary butyl hypochlorite andchlorine gas. Between these two, tertiary butyl hypochlorite isparticularly desirable. The reaction temperature and reaction time varyaccording to the particular thiazolidine azetidinone derivatives (3)reacted and the chlorinating agents used; but the temperature is usuallyset between -60° and 20° C., or more preferably between -30° to 10° C.,and the reaction is usually completed between 10 minutes to 2 hours.When tertiary butyl hypochlorite is used as the chlorinating agent, thereaction is enhanced by the addition of acids, such as hydrochloric acidand p-toluenesulfonic acid. When chlorine gas is used, it is recommendto add inorganic bases such as sodium hydrogen carbonate, potassiumcarbonate, and calcium oxide or propylene oxide as acid capturingagents.

Examples for organic solvents used in above method for converting thecompound of formula (3) to the compound of formula (1) of the presentinvention are lower alcohols such as methanol, ethanol, and isopropanol;ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and1,4-dioxane; halogenated hydrocarbon solvents such as dichloromethane,chloroform, and 1,2-dichloroethane; and esters such as ethyl acetate andmethyl formate.

For the method of the present invention where thiazolidine-azetidinonederivative represented by formula (1) is transformed into azetidinonederivative represented by formula (2), the former is dissolved in anorganic solvent containing a lower alcohol (such as methanol) at aconcentration of 1 mol/1 liter to 0.01 mol/1 liter. To this solution, anacid (such as hydrochloric acid) and the arylsulfinic acid of formula(4) or its metallic salt are added and a reaction is carried out. Thereaction temperature and reaction time are dependent on the type ofthiazolidine azetidinone derivative (1) reacted. However, a range of-20° to 50° C. (preferably or -5° to 25° C.) is desirable. The reactionis normally completed within 30 minutes to 10 hours. The quantity ofarylsulfinic acid (4) usually used ranges from 1.0 to 5.0 times(preferably from 1.05 to 1.20 times) the quantity ofthiazolidine-azetidinone derivative (1). Representative acids foraddition to the reaction include mineral acids such as hydrochloricacid, sulfuric acid, and phosphoric acid; and organic acids such astrifluoroacetic acid, methanesulfonic acid, and para-toluenesulfonicacid. Preferable among these acids are 1 to 20% methanol-methanesulfonicacid and 1 to 20% methanol-hydrochloric acid. The quantity of the acidadded ranges from 0.1 to 20 times, or more preferably from 5 to 10times, the quantity of thiazolidine-azetidinone (1).

For the organic solvent, a lower alcohol or a mixed solvent containingat least one type of lower alcohol is used. Examples of lower alcoholsinclude methanol, ethanol, and n-butanol. Examples of the organicsolvents mixed with lower alcohols are ketones such as acetone andmethyl ethyl ketone; nitriles such as acetonitrile and butylnitrile;ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran,chloroform, and 1,4-dioxane; halogenated hydrocarbon solvents such asnitromethane, dichloromethane, chloroform, 1,2-dichloroethane, andcarbon tetrachloride; aromatic solvents such as benzene, toluene, andchlorobenzene; esters such as ethyl acetate and methyl formate; andamides such as dimethylformamide and dimethylacetamide.

The compounds of the present invention, which have been produced by theabove-described method, are readily isolated and purified by a standardisolation procedures.

Example 1

This example describes the preparation of p-methoxybenzyl 2R-[(1R,5R)-3-benzyliden-4-formyl-6-oxo-4,7-diaza-2-thiabicyclo[3.2.0]heptan-7-yl]-3-chloromethyl-3-butenoate2'-oxide (1a) (the compound of formula (1) where R¹ =phenyl, R²=hydrogen and R³ =p-methoxybenzyl).

Five grams of compound (3a) (the compound of formula (3) where R¹=phenyl, R² =hydrogen and R³ =paramethoxybenzyl) was dissolved in 150 mlof methyl formate and cooled to -20° C. To this solution, 2.0 ml oft-butyl hypochlorite was added gradually and a reaction was allowed totake place at a temperature range of -20° to -10° C. for 30 minutes. Thereaction fluid was diluted in 200 ml of ethyl acetate, washed 3 times in200 ml of water, dried using sodium sulfate anhydride, and condensed invacuum. The residue was purified using column chromatography(acetonitrile-water, 3:2) with reversed phase C₁₈ (NakaraitesukuCosmoseal 75C₁₈ OPN, 500 g). Compound (1a) amounting to 4.75 g (88.8%)in a white powder form was obtained.

¹ H-NMR (CDCl₃)

δ 3.64 (s, 2H, CH₂ Cl), 3.78 (s, 3H, OCH₃), 5.04, 5.08, 5.28 (each s,each 1H, CH (COOCH₂ C₆ H₄ OCH₃) C (CH₂ Cl) ═CH₂), 5.07 (d, 1H, J=11.7Hz, CH₂ C₆ H₄ OCH₃), 5.15 (d, 1H, J=11.7 Hz, CH₂ C₆ H₄ OCH₃), 5.44 (d,1H, J=4.0 Hz, β-lactam), 6.16 (d, 1H, J=4.0 Hz, β-lactam), 6.86 (d, 2H,J=8.8 Hz, CH₂ C₆ H₄ OCH₃), 7.24 (d, 2H, J=8.8 Hz, CH₂ C₆ H₄ OCH₃),7.44-7.57 (m, 6H, ═CHC₆ H₅) 8.47 (s, 1H, HCO)

IR 1785, 1740, 1690 cm⁻¹

Example 2

This example describes the preparation of p-methoxybenzyl 2R-[(1R,5R)-3-benzyliden-4-acetyl-6-oxo-4, 7-diaza-2-thiabicyclo[3.2.0]heptan-7-yl]-3-chloromethyl-3-butenoate 2'-oxide (1b) (thecompound of formula (1) where R¹ =phenyl, R² =methyl and R³=p-methoxybenzyl).

Five grams of compound (3b) (the compound of formula (3) where R¹=phenyl, R² =methyl, R³ =p-methoxybenzyl) was dissolved in 150 ml ofmethyl formate and cooled to -50° C. To this solution, 2.2 ml of t-butylhypochlorite was gradually added and a reaction was allowed to takeplace at -50° to -40° C. for 60 minutes. Through a procedure similar tothat described in Example 1, 4.65 g (87.3%) of compound (1b) wasobtained in a white powder form.

¹ H-NMR (CDCl₃)

δ 2.35 (s, 3H, CH₃ CO), 3.49 (s, 2H, CH₂ Cl), 3.80 (s, 3H, OCH₃), 5.02,5.20 (each s, 2H, 1H, CH (COOCH₂ C₆ H₄ OCH₃) C (CH₂ Cl) ═CH₂), 5.09 (d,1H, J=11.7 Hz, CH₂ C₆ H₄ OCH₃), 5.15 (d, 1H, J=11.7 Hz, CH₂ C₆ H₄ OCH₃),5.34 (d, 1H, J=4.0 Hz, β-lactam), 6.37 (d, 1H, J=4.0 Hz, β-lactam), 6.87(d, 2H, J=8.8 Hz, CH₂ C₆ H₄ -OCH₃), 7.24 (d, 2H, J=8.8 Hz, CH₂ C₆ H₄OCH₃), 7.38 (s, 1H, ═CHC₆ H₅), 7.40-7.65 (m, 5H, ═ CHC₆ H₅)

IR 1785, 1740, 1690 cm⁻¹

Example 3 Synthesis of Compound (1a)

Two grams of compound (3a) was dissolved in 100 ml of methylene chlorideand cooled to 0° C. To the solution, 0.5 ml of 1N-hydrogenchloride/methanol and then 0.8 ml of t-butyl hypochlorite were added anda reaction was allowed to take place at a temperature range of 0° to 5°C. for 30 minutes. Procedures similar to those described in Example 1were conducted to obtain 1.79 g (83.7%) of compound (1a).

Example 4

Compound (3a), 7.8 g, was dissolved in 150 ml of dioxane. To thesolution, 4.4 ml of propylene oxide was added and the mixture was cooledto 10° C. Over the solution, 22 ml of a carbon tetrachloride solution ofchlorine (concentration at 1.8M) was gradually dripped therein. After areaction at a temperature range of 10° to 12° C. for 5 hours, thereaction fluid was condensed In vacuum without further processing. Theresidue was purified by procedures similar to those described forExample 1 to obtain 4.34 g (52.1%) of compound (1a).

Example 5

This example describes the preparation of p-methoxybenzyl2-(3-amino-4-(p-toluene)sulfonylthio-2-azetidinon-1-yl)-3-chloromethyl-3-butenoate(2a) (the compound of formula (2) where R¹ =p-methoxybenzyl andAr=p-tolyl).

First, 500 mg of compound (1 a) (R¹ =phenyl, R² =hydrogen, R³=p-methoxybenzyl) was dissolved in a mixture of 1.5 ml of methylenechloride and 10 ml of methanol. While being chilled, 1 ml of6N-hydrochloric acid and 166 mg of paratoluenesulfinic acid were addedto the solution and a reaction was allowed to take place at ambienttemperature for 4 hours. The reaction fluid was poured into a mixture of50 ml of methylene chloride and 50 ml of water. Following fluidseparation, the aqueous layer was extracted in 10 ml of methylenechloride and combined with the organic layer, which was then dried byusing sodium sulfate anhydride and condensed in vacuum. The residue waspurified using cola chromatography (acetonitrile-water 3:2) withreversed phase C₁₈ (Nakaraitesuku Cosmoseal 75 C₁₈ OPN, 50 g), whichresulted in the production of 428 mg (84%) of compound (2a) in the formof light yellow syrup.

¹ H-NMR (CDCl₃)

δ 1.78 (bs, 2H, NH₂), 2.44 (s, 3H, SO₂ C₆ H₄ CH₃), 3.80 (s, 3H, CH₂ C₆H₄ OCH₃), 4.07 (s, 2H, CH₂ C₆ H₄ OCH₃), 4.63 (d, 1H, J=4.5 Hz,β-lactam), 4.93, 5.07, 5.37 (each s, each 1H, CH (COOCH₂ C₆ H₄ OCH₃) C(CH₂ Cl) ═CH₂), 5.10 (d, 1H, J=10.8 Hz, CH₂ Cl), 5.17 (d, 1H, J=10.8 Hz,CH₂ Cl), 5.53 (d, 1H, J=4.5 Hz, β-lactam), 6.89 (d, 2H, J=9.0 Hz, CH₂ C₆H₄ OCH₃), 7.28 (d, 2H, J=9.0 Hz, CH₂ C₆ H₄ OCH₃), 7.33 (d, 2H, J= 8.4Hz, SO₂ C₆ H₄ CH₃), 7.77 (d, 2H, J=8.4 Hz, SO₂ C₆ H₄ CH₃)

IR 3400, 3340, 1775, 1740, 1335, 1145 cm⁻¹

Example 6

This example describes the preparation of p-methoxybenzyl2-(3-amino-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-chloromethyl-3-butenoate(2b) (the compound of formula (2) where R¹ =p-methoxybenzyl andAr=phenyl).

First, 500 mg of compound (1a) (R¹ --phenyl, R² =hydrogen, R³=p-methoxybenzyl) was dissolved in a mixture of 1.5 ml of methylenechloride and 4 ml of methanol. While the solution was chilled, 6 ml of1N-hydrogen chloride/methanol and 213 mg of sodium benzenesulfinatedihydrate were added and a reaction was allowed to take place at ambientfor 3 hours. Procedures similar to those of Example 1 were conducted toobtain 443 mg (87%) of compound (2b) in the form of a light yellowsyrup.

¹ H - NMR (CDCl₃)

δ 1.80 (bs, 2H, NH₂), 3.80 (s, 3H, CH₂ C₆ H₄ OCH₃), 4.05 (s, 2H, CH₂ C₆H₄ OCH₃), 4.63 (d, 1H, J=4.5 Hz, β-lactam), 4.92, 5.01, 5.33 (each s,each 1H, CH (COOCH₂ C₆ H₄ OCH₃) C (CH₂ Cl) ═CH₂), 5.09 (d, 1H, J=10.8Hz, CH₂ Cl), 5.16 (d, 1H, J=10.8 Hz, CH₂ Cl), 5.55 (d, 1H, J=4.5 Hz,β-lactam), 6.89 (d, 2H, J=9.0 Hz, CH₂ C₆ H₄ OCH₃), 7.28 (d, 2H, J=9.0Hz, CH₂ C₆ H₄ OCH₃), 7.51-7.89 (5h, m, SO₂ C₆ H₅)

IR 3400, 3340, 1775, 1740, 1335, 1145 cm⁻¹

Example 7

This example describes the preparation of p-methoxybenzyl2-(3-amino-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-chloromethyl-3-butenoate(2b) (R¹ =p-methoxybenzyl, Ar=phenyl).

One gram of compound (1b) (R¹ =phenyl, R² =methyl, R³ =p-methoxybenzyl)was dissolved in a mixture of 3 ml of methylene chloride and 8 ml ofmethanol. While the solution was being chilled, 12 ml of 1N-hydrogenchloride/methanol and 450 mg of sodium benzenesulfinate dihydrate wereadded and a reaction was allowed to take place at ambient for 12 hours.Procedures similar to those of Example 1 were performed to obtain 797 mg(82%) of compound (2b).

Example 8

This example describes the preparation of p-methoxybenzyl2-(3-amino-4-(p-toluene)sulfonylthio-2-azetidinon-1-yl)-3-chloromethyl-3-butenoate(2a).

First, 750 mg of compound (1a) (R¹ =phenyl, R² =hydrogen, R³=p-methoxybenzyl) was dissolved in a mixture of 2.3 ml of methylenechloride and 15 ml of methanol. While the solution was being chilled,0.331 ml of methanesulfonic acid and 686 mg of sodium benzene-sulfinatewere added and a reaction was allowed to take place at the sametemperature for 18 hours. The reaction fluid was added to a mixture of75 ml of methylene chloride and 75 ml of water. After separation of thefluid, the organic layer was dried using anhydrous sodium sulfate andcondensed in vacuum. The residue was purified by using columnchromatography (acetonitrile-water 3:2) with reversed phase C₁₈(Nakaraitesuku Cosmoseal 75 C₁₈ OPN, 80 g). Compound (2a) in a quantityof 686 mg (91%) was obtained in the form of a light yellow syrup.

Thiazolidine azetidinone derivatives expressed by general formula (1)and azetidinone derivatives expressed by general formula (2) of thepresent invention are easily transformed into important syntheticintermediates (5) of various cephalosporins via aforementioned reactionscheme (A) which was introduced by the present inventors. For thisreason, the present invention is extremely valuable in thepharmaceutical industry. Furthermore, inexpensive penicillins may beused as the starting material, which contributes significantly to areduction in the manufacturing costs of various cephalosporinantibiotics.

We claim:
 1. A method of producing a cephalosporin derivative havingformula (5): ##STR12## comprising first preparing a compound havingformula (1): ##STR13## by dissolving a thiazolidine derivative havingformula (3): ##STR14## in an organic solvent at a concentration of thethiazolidine derivative (3) to the solvent of 0.01 mol/liter to 1mol/liter, followed by reaction with a chlorinating agent at atemperature between 60° C. and 20° C.;dissolving the resultingthiazolidine derivative (1) in an organic solvent at a concentration ofthe thiazolidine derivative (1) to the solvent of 0.01 mol/liter to 1mol/liter, and adding an arylsulfinic acid in an amount of 1.0 to 5.0times an amount of the thiazolidine derivative (1) and an another acidin an amount of 0.1 to 20 times the amount of the thiazolidinederivative (1), and carrying out a reaction at a temperature of -20° C.to 50° C. to form a compound having formula (2): ##STR15## and addingthe compound having formula (2) to a solvent containing a base having amolar quantity of about 1.1 to about 1.5 relative to the compound (2)and carrying out a reaction at a temperature between about -50° and 5°C. to form the compound of formula (5), wherein Ar is an aryl group, R¹is a member selected from the group consisting of aryl group and aryloxygroup, R² CO is a carboxy residue, and R³ is a member selected from thegroup consisting of a hydrogen atom and a carboxylic protective group.2. The method of preparing a cephalosporin derivative according to claim1, wherein the solvent for the thiazolidine derivative (3) is a memberselected from the group consisting of methanol, ethanol, isopropanol,diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane,dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate andmethyl formate.
 3. The method of preparing a cephalosporin derivativeaccording to claim 1, wherein the chlorinating agent is a memberselected from the group consisting of tertiary butyl hypochlorite andchlorine gas.
 4. The method of preparing a cephalosporin derivativeaccording to claim 1, wherein the reaction with the chlorinating agentis carried out for between 10 minutes and 2 hours.
 5. The method ofpreparing a cephalosporin derivative according to claim 1, wherein thesolvent for the thiazolidine derivative (1) is a lower alcohol.
 6. Themethod of preparing a cephalosporin derivative according to claim 1,wherein the other acid is a member selected from the group consisting ofhydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid,methanesulfonic acid and para-toluenesulfonic acid.
 7. The method ofpreparing a cephalosporin derivative according to claim 1, wherein thearylsulfinic acid has the formula Ar--SO₂ H where Ar is an aryl group.8. The method of preparing a cephalosporin derivative according to claim1, wherein the reaction of the thiazolidine derivative (1) with thearylsulfinic acid and the another acid is carried out for 30 minutes to10 hours.
 9. The method of preparing a cephalosporin derivativeaccording to claim 1, wherein the solvent for the compound havingformula (2) is a member selected from the group consisting ofdimethylformamide, dimethylacetamide, methanol, ethanol, 2-propanol,acetonitrile, butyronitrile, acetone and methyl ethyl ketone.
 10. Themethod of preparing a cephalosporin derivative according to claim 1,wherein the base is a member selecting from the group consisting ofammonia, ammonia water, potassium hydroxide, sodium hydroxide, potassiumacetate, sodium acetate, triethylamine, pyridine,1,8-diazabicyco[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene,potassium iodide and sodium iodide.
 11. The method of preparing acephalosporin derivative according to claim 1, wherein the reaction ofthe compound of formula (2) in a solvent containing base is carried outfor about 5 to about 30 minutes.